1300 Cardiovascular Drugs Pharmacopoeias. In Jpn and US. Uses and Administration dine, but authorities have differed as to whether the drug should USP 31 (Guanabenz Acetate). A white or almost white powder Guanadrel is an antihypertensive with actions and uses similar to be stopped before elective surgery. Former US licensed product with not more than a slight odour. Sparingly soluble in water and those of guanethidine (below). After oral administration, gua- information recommended stopping up to 2 or 3 weeks before- in 0.1N hydrochloric acid; soluble in alcohol and in propylene nadrel acts within 2 hours with the maximum effect after 4 to 6 hand. In patients undergoing emergency procedures or where glycol. A 0.7% solution in water has a pH of 5.5 to 7.0. Store in hours. The hypotensive effect is reported to last for 4 to 14 hours treatment has not been interrupted large doses of atropine should airtight containers. Protect from light. following a single dose. It has been given orally as the sulfate in be given before induction of anaesthesia. the management of hypertension, although it has largely been su- Patients undergoing treatment with eye drops containing Adverse Effects and Precautions perseded by other drugs less likely to cause orthostatic hypoten- As for Clonidine Hydrochloride, p.1247. guanethidine should be examined regularly for signs of conjunc- sion. tival damage. Overdosage. Overdosage with guanabenz has been reported.1 Preparations The main symptoms were lethargy, drowsiness, bradycardia, and Interactions hypotension. A 45-year-old woman who had taken 200 to USP 31: Guanadrel Sulfate Tablets. Patients taking guanethidine may show increased sensitivity to 240 mg of guanabenz with alcohol recovered after gastric lavage the action of adrenaline, amfetamine, and other sympathomimet- and intravenous fluids; a 3-year-old child who had taken 12 mg ics, resulting in exaggerated pressor effects. The hypotensive ef- fects may also be antagonised by tricyclic antidepressants, of guanabenz responded to atropine and dopamine. Naloxone Guanethidine Monosulfate (USAN, rINNM) had little effect in either patient. MAOIs, and phenothiazine derivatives and related antipsychot- Guanéthidine, monosulfate de; Guanethidine Monosulphate ics (although phenothiazines may also exacerbate orthostatic hy- 1. Hall AH, et al. Guanabenz overdose. Ann Intern Med 1985; 102: (BANM); Guanethidini Monosufas; Guanethidini monosulfas; potension, which may be more relevant clinically). In the UK 787–8. Guanethidini Sulfas; Guanethidin-monosulfát; Guanetidiinimono- licensed product information suggests that MAOIs should be Interactions sulfaatti; Guanetidinmonosulfat; Guanetidin-monoszulfát; Guane- stopped at least 14 days before beginning guanethidine, although As for Clonidine Hydrochloride, p.1248. tidino monosulfatas; Monosulfato de guanetidina; NSC-29863 in the USA a minimum of a week has been recommended as ad- Pharmacokinetics (guanethidine hemisulfate); Su-5864 (guanethidine hemisulfate). equate. It has been reported that oral contraceptives may reduce About 75% of an oral dose of guanabenz is absorbed and under- 1-[2-(Perhydroazocin-1-yl)ethyl]guanidine monosulfate. the hypotensive action of guanethidine. Use of digoxin or other goes extensive first-pass metabolism. Peak plasma concentra- digitalis derivatives with guanethidine may cause excessive Гуанетидина Моносульфат bradycardia. tions occur about 2 to 5 hours after a dose. It is about 90% bound C H N ,H SO = 296.4. to plasma proteins. Guanabenz is mainly excreted in urine, al- 10 22 4 2 4 The hypotensive effects of guanethidine may be enhanced by thi- CAS — 55-65-2 (guanethidine); 60-02-6 (guanethidine azide diuretics, other antihypertensives, and levodopa. Alcohol most entirely as metabolites, with less than 1% as unchanged hemisulfate); 645-43-2 (guanethidine monosulfate). may cause orthostatic hypotension in patients taking guanethi- drug; about 10 to 30% is excreted in faeces. The average elimi- ATC — C02CC02; S01EX01. dine. nation half-life is reported to range from 4 to 14 hours. ATC Vet — QC02CC02; QS01EX01. Uses and Administration Pharmacokinetics Guanethidine is variably and incompletely absorbed from the Guanabenz is an alpha2-adrenoceptor agonist with actions and uses similar to those of clonidine (p.1248). It is used in the man- H gastrointestinal tract with less than 50% of the dose reaching the N NH2 systemic circulation. It is actively taken up into adrenergic neu- agement of hypertension (p.1171), either alone or with other N antihypertensives, particularly thiazide diuretics. rones by the mechanism responsible for noradrenaline reuptake. A plasma concentration of 8 nanograms/mL is reported to be Guanabenz is given orally as the acetate, but doses are usually NH necessary for adrenergic blockade, but the dose required to expressed in terms of the base. Guanabenz acetate 5 mg is equiv- achieve this varies between individuals due to differences in ab- alent to about 4 mg of guanabenz. (guanethidine) sorption and metabolism. Guanethidine is partially metabolised In hypertension, the usual dose is 4 mg twice daily initially; the in the liver, and is excreted in the urine as metabolites and daily dose may be increased by amounts of 4 to 8 mg every 1 to Pharmacopoeias. In Eur. (see p.vii), Jpn, and US. unchanged guanethidine. It has a terminal half-life of about 5 2 weeks according to response. Doses of up to 32 mg twice daily Chin. includes the hemisulfate. days. Guanethidine does not penetrate the blood-brain barrier have been used. Ph. Eur. 6.2 (Guanethidine Monosulphate). A colourless crys- significantly. Preparations talline powder. Freely soluble in water; practically insoluble in Uses and Administration USP 31: Guanabenz Acetate Tablets. alcohol. A 2% solution in water has a pH of 4.7 to 5.5. Protect Guanethidine is an antihypertensive that acts by selectively in- from light. Proprietary Preparations (details are given in Part 3) hibiting transmission in postganglionic adrenergic nerves. It is USP 31 (Guanethidine Monosulfate). A white to off-white crys- Braz.: Lisapres; USA: Wytensin. believed to act mainly by preventing the release of noradrenaline talline powder. Very soluble in water; sparingly soluble in alco- at nerve endings. Guanethidine causes the depletion of noradren- hol; practically insoluble in chloroform. A 2% solution in water aline stores in peripheral sympathetic nerve terminals but does has a pH of 4.7 to 5.7. not prevent the secretion of catecholamines by the adrenal me- Guanadrel Sulfate (USAN, rINNM) Adverse Effects dulla. CL-1388R; Guanadrel, Sulfate de; Guanadrel Sulphate; Gua- The commonest adverse effects of guanethidine are severe pos- When given orally its maximal effects may take 1 to 3 weeks to nadreli Sulfas; Sulfato de guanadrel; U-28288D. 1-(Cyclohexane- tural and exertional hypotension and diarrhoea which may be appear on continued dosing and persist for 1 to 3 weeks after spiro-2′-[1′,3′]dioxolan-4′-ylmethyl)guanidine sulfate; 1-(1,4-Di- particularly troublesome during the initial stages of therapy and treatment has been stopped. It causes an initial reduction in car- oxaspiro[4.5]dec-2-ylmethyl)guanidine sulfate. during dose adjustment. Dizziness, syncope, muscle weakness, diac output but its main hypotensive effect is to cause peripheral and lassitude are liable to occur, especially on rising from sitting vasodilatation; it reduces the vasoconstriction which normally Гуанадрела Сульфат or lying. Orthostatic hypotension may be severe enough to pro- results from standing up and which is the result of reflex sympa- (C10H19N3O2)2,H2SO4 = 524.6. voke angina, renal impairment, and transient cerebral ischaemia. thetic nervous activity. In the majority of patients it reduces CAS — 40580-59-4 (guanadrel); 22195-34-2 (guanadrel Other frequent adverse effects are bradycardia, failure of ejacu- standing blood pressure but has a lesser effect on supine blood sulfate). lation, fatigue, headache, and salt and water retention and oede- pressure. When applied topically to the eye guanethidine reduces ma, which may be accompanied by breathlessness and may oc- the production of aqueous humour. casionally precipitate overt heart failure. Guanethidine is used in the management of hypertension NH Nausea, vomiting, dry mouth, nasal congestion, parotid tender- (p.1171). Eye drops of guanethidine have been used for open- ness, blurring of vision, depression, myalgia, muscle tremor, par- angle glaucoma (p.1873) and for lid retraction associated with O aesthesias, hair loss, dermatitis, disturbed micturition, priapism, hyperthyroidism. Guanethidine has also been used in the man- N NH2 H2SO4 aggravation or precipitation of asthma, and exacerbation of pep- agement of neuropathic pain syndromes (see below). H tic ulcer disease have also been reported. Guanethidine may pos- Guanethidine is used in the treatment of hypertension when other O sibly cause anaemia, leucopenia, and thrombocytopenia. 2 drugs have proved inadequate, but it has largely been superseded When guanethidine is used as eye drops, common adverse ef- by other drugs less likely to cause orthostatic hypotension. Tol- fects are conjunctival hyperaemia and miosis. Burning sensa- erance to guanethidine has occurred in some patients; this may Pharmacopoeias. In US. tions and ptosis have also occurred. Superficial punctate keratitis be countered by concomitant diuretic therapy. USP 31 (Guanadrel Sulfate). A white to off-white crystalline has been reported particularly after prolonged use of high